The effect of cannabinoids on wound healing: A review

Abstract Background and Aims Cannabis and its various derivatives are commonly used for both recreational and medicinal purposes. Cannabinoids have been shown to have anti‐inflammatory properties. Inflammation is an important component of wound healing and the effect of cannabinoids on wound healing has become a recent topic of investigation. The objective of this article is to perform a comprehensive review of the literature to summarize the effects of cannabinoids on wound healing of the skin and to guide future avenues of research. Methods A comprehensive literature review was performed to evaluate the effects of cannabinoids on cutaneous wound healing. Results Cannabinoids appear to improve skin wound healing through a variety of mechanisms. This is supported through a variety of in vitro and animal studies. Animal studies suggest application of cannabinoids may improve the healing of postsurgical and chronic wounds. There are few human studies which evaluate the effects of cannabinoids on wound healing and many of these are case series and observational studies. They do suggest cannabinoids may have some benefit. However, definitive conclusions cannot be drawn from them. Conclusion While further human studies are needed, topical application of cannabinoids may be a potential therapeutic option for postsurgical and chronic wounds.

Today, cannabis is a term that is often used interchangeably with marijuana.However, this is an incorrect attribution.Although the precise taxonomy has not been agreed upon, the plant used in the development of marijuana is considered either a species (Cannabis indica) in the larger Cannabis genus, or a subspecies (C.sativa subsp.indica) of the Cannabis sativa species.The plant responsible for cannabis derived products is recognized as either the species Cannabis sativa in the former taxonomy or C. sativa subsp.sativa in the latter. 7,8For the purposes of this review, we will accept the former taxonomy for simplicity's sake, recognizing the ongoing debate in this field.
Regardless of the taxonomy, a vast array of chemicals has been identified from cannabis plants.Of these, the cannabinoids have been an area of great interest.These cannabinoids include delta-9 tetrahydrocannabinol (THC), the psychoactive compound that is predominantly found in the C. indica plant and is the focus of regulations, as well as cannabidiol (CBD), predominantly found in the C. sativa plant, which is the focus of industrial uses and nonpsychotropic medical research. 9,102][13][14] Cannabis and its components have been shown to have anti-inflammatory properties. 15As inflammation is an important component within the process of wound healing, the effect of cannabis and its constituents on wound healing has become a topic of renewed investigation. 16e endocannabinoid system is centered around the cannabinoid 1 (CB 1 ) and cannabinoid 2 (CB 2 ) receptors.Traditionally, CB 1 was reported to be found within the central nervous system while CB 2 was located within peripheral tissues and immune cells. 17However, recent studies have shown this is not always the case and CB 1 receptors may also be found peripherally. 18Additionally, while there are numerous natural cannabinoids which have been isolated and studied, there has been a movement to develop selective CB 1 and CB 2 agonists and antagonists which has furthered the understanding of how cannabinoids could play a role in cellular homeostasis. 19,20is review describes a variety of CB 1 and CB 2 ligands including the CB 1 agonist, arachidonoyl-chloro-ethanolamide (ACEA), the CB 2 agonists JWH015, JWH133, and GP1a and the nonspecific CB receptor agonist WIN55,212-2.Additionally, there are some compounds that interact with multiple receptors such as VCE-004.8, which is a CB 2 and PPARγ agonist.Finally, there are a variety of antagonists such as AM251 and AM630, which are CB 1 and CB 2 receptor antagonists, respectively (Table 1).These compounds can have varying actions on the CB receptors leading to complex downstream effects.However, the increased understanding of the roles of the CB 1 and CB 2 and the development of selective receptor ligands have allowed for further understanding of the effect of cannabinoids on the wound healing process.
The goal of this review article is to perform a comprehensive review of the literature including in vitro, animal, and human studies, and to summarize the effects of cannabinoids on wound healing of the skin to guide potential future avenues of translational research.

| METHODS
A comprehensive review of the literature was performed using OVID Medline.Search terms included wound healing or wound inflammation and cannabis, Cannabis sativa, cannabidiol, cannabinoids, tetrahydrocannabinol, marijuana, hashish, or hemp.Primary basic science, animal, and human studies were identified, and abstracts were reviewed by the primary authors.Review articles and studies evaluating wound healing unrelated to the skin were excluded.Only articles in English and full text articles were included for evaluation (Figure 1).The included articles were evaluated by the authors and summarized below.

| RESULTS
A total of 32 articles met the inclusion criteria.There were 13 in vitro studies, 13 in vivo studies, and six human studies (Tables 2-4).The studies are summarized below.

| In vitro studies
Many studies have evaluated the effects of cannabinoids and CB receptor ligands on keratinocyte and fibroblast cells lines.Sangiovanni et al. 25 treated keratinocyte and fibroblast cell lines with tumor necrosis factor-α (TNF-α) and either C. sativa or cannabidiol (CBD) and evaluated the effects of the proinflammatory stimulus.They noted that C. sativa inhibited the proinflammatory cytokine release to varying degrees whereas CBD showed some inhibition but not to the same degree as C. sativa.Finally, they showed that both compounds were able to downregulate genes which were overexpressed after TNF-α treatment. 25Miller et al. 31 treated bone marrow-derived stem cells, adipose-derived stem cells, and porcine primary fibroblasts with THC and CBD and noted improved cell migration.Additionally, they found when porcine primary fibroblasts where exposed to CBD, there was a 75% faster wound closure. 31Ramot et al. 21found the expression of keratin 6, a protein which downregulates keratinocyte migration, decreased when keratinocytes were treated with arachidonoyl-chloro-ethanolamide (ACEA), a CB 1 agonist, and increased when keratinocytes were treated with a CB 1 antagonist.They hypothesized the effects of CB 1 stimulation on keratin 6 could be exploited to modulate reepithelialization in wound healing. 21Bort et al. 23 showed that JWH015, a CB 2 agonist, reduced proinflammatory cytokines and increased antiinflammatory compounds, such as transforming growth factor-β (TGF-β), in keratinocytes and fibroblasts treated with lipopolysaccharide, and induced a faster gap closure during a scratch In vivo studies Year Author Cannabinoid type Findings Zheng et al. 33 N/A Created wounds on mice: CB 2 was present at baseline in uninjured tissue and its expression increased after wound injury and peaked at 3-5 days Li et al. 34 Intraperitoneal GP1a and AM630 Mice wounds after treatment with a CB 2 agonist showed less collagen, decreased skin thickness, and downregulation of fibrosis genes compared to an antagonist Wang et al. 35 Intraperitoneal GP1a and AM630 Mice wounds after treatment with a CB 2 agonist showed less wound contraction, accelerated reepithelialization, thinner dermal scar with more slender collagen fibers while the antagonist showed delayed reepithelialization Wohlman et al. 36 N/A Mice wounds treated with sulfur and nitrogen mustard led to upregulation of CB 1 and CB 2 and findings suggested CB 1 may regulate keratinocyte proliferation whereas CB 2 may regulate keratinocyte differentiation Del Rio et al. 37 Intraperitoneal VCE-004.8 or AM630 A CB 2 and PPARγ agonist reduced collagen synthesis, deposition, and myofibroblast differentiation and reduced skin fibrosis when mice were treated with bleomycin (to create an animal model for systemic scleroderma) Mehrabani et al. 38 Topical "New Formula" (included hemp oil) Mice burn wounds treated with new formula showed increased wound contraction and decreased epithelialization time Du et al. 39 Intraperitoneal JWH133, GP1a, and AM630 CB 2 led to an anti-inflammatory response by inhibiting proinflammatory M1 macrophages rather than increasing activity of anti-inflammatory M2 macrophages.
Klein et al. 40 Intraperitoneal CBD Mice wounds after CBD treatment showed lower inflammatory infiltrate on day 3. On day 7, they noted increased tissue organization and marked epithelial changes Koyama et al. 41 Topical beta-caryophyllene Mice wounds treated with CB 2 ligand showed improved reepithelialization.However, other findings suggested these may not be directly related to CB 2 activation.
Casares et al. 42 Topical CBD Mice skin treated with topical CBD showed increased levels of HMOX1 and wound repair keratins in mice skin McIver et al. 43 Topical CBD Horse wounds treated with either unique manuka factor versus topical CBD showed no difference in healing rates Ruhl et al. 24 N/A CB 1 knockout mice showed delayed wound healing and CB 2 knockout mice had increased proinflammatory cytokines but no changes to tissue regeneration Zhao et al. 44 Topical GP1a hydrogel GP1a hydrogel to mice wounds decreased inflammation and fibrogenesis and increased wound closure and reepithelialization  45 Topical CBD Case series: patients with epidermolysis bullosa had improved symptoms Palmieri et al. 46 Topical CBD Retrospective review: patients with various cutaneous disorders had improved symptoms Maida et al. 47 Topical CBD, terpenes, and flavonoids Prospective cohort study: patients with nonuremic calciphylaxis leg ulcers who failed other treatments had a good response Maida et al. 48opical CBD, terpenes, and flavonoids Prospective cohort study: patients with venous leg ulcers who failed other treatments had a good response Diaz et al. 49 Oral THC and CBD oils Case report: patient with pressure ulcer refractory to treatment for 5 years improved incidentally after starting CBD and THC oil Schrader et al. 50opical, oral, and inhaled cannabinoids Cross-sectional survey: patients with epidermolysis bullosa had improvement in their symptoms test assay.The cells were treated with CB 1 and CB 2 antagonists and they noted these effects were likely modulated through both receptors.Additionally, they utilized porcine skin as an ex vivo skin model and found that JWH015 had sustained and low transdermal distribution which may have promising therapeutic potential. 23hl et al. 24 treated cells with lipopolysaccharides and observed that co-treatment with CBD reduced the oxidative stress on cells.
Lipopolysaccharides also inhibited further cell differentiation, and this was attenuated by CBD. 24They then evaluated the effects of WIN55,212-2, a nonspecific CB receptor ligand, and JWH133, a CB₂ agonist, on multipotent mesenchymal stromal cells from subcutaneous adipose tissue and noted these compounds had varying effects on their differentiation.Interestingly, they also noted that both WIN55,212-2 and JWH133 increased hepatocyte growth factor which is known to stimulate migration and proliferation of keratinocytes and is important in cutaneous wound healing. 26They then treated macrophages and mesenchymal stromal cells with lipopolysaccharides and evaluated the inflammatory response after treatment with the endocannabinoids anandamide, 2-arachidonoylglycerol, and JWH133 and noted they decreased the inflammatory response of M1 macrophages.This decrease was less significant in activated mesenchymal stromal cells. 28rreia-Sa et al. 27 collected skin samples from patients who underwent body contouring surgery and noted lower levels of anandamide were found in hypertrophic scars compared to normal scars.They suggested that reduced anandamide is potentially related to increased inflammation or a prolonged inflammatory phase which predisposed patients to scar hypertrophy. 27They then collected skin samples from abdominoplasty patients and treated cells with ACEA and AM251, a CB 1 antagonist.They noted increased collagen deposition with ACEA and decreased collagen deposition with AM251.Additionally, they performed ex vivo reepithelization studies and noted ACEA speeds reepithelialization. 29 This same group then evaluated the effects of TGF-β on fibroblast cells and treated these cells with JWH133 and AM630, a CB 2 antagonist.They noted TGF-β increased α-SMA expression, which is a marker for myofibroblast differentiation, and increased expression of CB 2 .Both JWH133 and AM630 led to decreased collagen deposition and α-SMA expression after exposure to TGF-β.When the fibroblasts were not treated with TGF-β, only AM630 led to decreased collagen deposition and α-SMA expression.This study showed the complex interplay of CB 2 on the wound healing process. 51yrczewska et al. 22 performed scratch test assays with hydrophobic flax fiber extract, which contained CBD, and demonstrated improved wound healing via inhibition of chronic inflammation and promotion of extracellular matrix remodeling and skin cell migration.The authors suggested the improvement is secondary to two components: presence of CBD and the content of phytosterol.
Atalay et al. 30 treated keratinocytes with hydrogen peroxide which led to a proinflammatory state which was partially attenuated by CBD.
Some authors also evaluated how CBD may assist in modulating wound healing dressings.Antezana et al. 32 developed collagen hydrogels loaded with silver nanoparticles and C. sativa extract.They found this compound reduced bacterial growth and provided a matrix that allowed for tissue growth.The silver nanoparticles and collagen gels were shown to be toxic to human cell lines; however, with the addition of C. sativa there was improved biocompatibility due to decreased cell toxicity and continued antimicrobial activity. 32

| Animal studies
Ruhl et al. 52 evaluated CB 1 and CB 2 knockout mice by creating a wound which was analyzed over a 2-week period.They found CB 2 knockout mice had increased proinflammatory cytokines but no changes in tissue regeneration.CB 1 knockout mice showed delayed wound closure early in the healing process suggesting that while previously not considered as present within the immune system, CB 1 does play a role in modulating inflammation during wound healing. 52eng et al. 33 created a 1.5 cm incision on mice and evaluated these wounds at variable time intervals for the for the timing of CB 2 expression.They found that while CB 2 was present at baseline within uninjured tissue, its expression within inflammatory cells significantly increased after wound injury.They found macrophages and myofibroblasts with CB 2 reached their maximum numbers at 3 and 5 days, respectively. 33They then evaluated the effects of CB 2 activation on fibrogenesis.They created two 6 mm wounds on mice dorsum and subsequently treated the mice with GP1a, a CB 2 agonist, AM630, and a control, intraperitoneally.They found mice treated with GP1a had less collagen deposition, more slender collagen fibers, and decreased skin thickness whereas those treated with AM630 showed opposing results.Additionally, the GP1a group showed decreased expression of cytokines involved in fibrogenesis and downregulation of fibrosis associated genes whereas the AM630 group showed increased levels of these cytokines and upregulation of these genes. 34In another study, they evaluated the effects of GP1a and AM630 on wound inflammation and reepithelialization after wounds were created on mice.When treated with AM630, there was delayed reepithelization.When treated with the GP1a, they noted decreased wound contraction, accelerated reepithelialization, thinner dermal scar with more slender collagen fibers, increased interferon-γ, and decreased epidermal hypertrophy, granulation tissue, inflammatory infiltration, and expression of inflammatory proteins.Additionally, there was more epithelial to mesenchymal transition with increased ability for cell migration.Overall, these findings suggest CB 2 receptor activation attenuates wound inflammation and fibrogenesis. 35In 2018, they created cutaneous wounds on mice and treated them with JWH133, GP1a, and AM630 to evaluate the specific macrophage response noted in the wound bed.They noted that while both M1 and M2 macrophages were present within the wound bed after injury, M1 macrophages were seen earlier in the injury process whereas M2 macrophages were more present in the later stages.They also found the presence of M1 macrophages was likely related to expression of the CB 2 and suggested its activation led to an anti-inflammatory response by inhibiting the PARIKH ET AL.
| 5 of 10 proinflammatory M1 macrophages rather than increasing the activity of the anti-inflammatory M2 macrophages. 39Overall, the studies from this group describe the critical role that CB 2 activation plays in improved wound healing.
Klein et al. 40 created oral tongue ulcers in rats and treated them with varying concentrations of CBD and a control, intraperitoneally.
They grossly and pathologically analyzed the wound at days 3 and 7.
They noted no gross difference between the groups.However, they found that at day 3 the groups treated with CBD had a significantly lower level of inflammatory infiltrate compared to the vehicle groups, but this change was not noted on day 7. Interestingly, they noted increased tissue organization at day 7 and more marked epithelial changes in the CBD group suggesting its favorable effects on reepithelization. 40ao et al. 44 created a hydrogel containing Gp1a and administered this locally to 4 mm punch wounds created on mice.They found after treatment with the Gp1a hydrogel, there was increased levels of CB 2 expression 4 and 8 days after surgery suggesting the hydrogel allowed for gradual release of Gp1a over 8 days.Additionally, the Gp1a hydrogel group showed decreased messenger RNA (mRNA) expression of inflammatory cytokines, fibrosis, skin thickness, and mRNA and protein levels of collagen I compared to the control.
Finally, the Gp1a hydrogel group showed faster wound healing, longer epithelial sheets, and increased levels of protein markers characteristic of epithelial-mesenchymal transition. 44yama et al. 41 treated mice wounds with beta-caryophyllene, a compound present in herbs and spices and a ligand of CB 2 .They noted improved reepithelialization, increased markers of reepithelization, and increased cell proliferation throughout the wound bed.
However, while some of their experiments suggested these changes may be related to CB 2 activation, others suggested they may not be directly related to CB 2 activation given that CB 2 was downregulated in the beta-caryophyllene group. 41Wohlman et al. 36 evaluated the effects of sulfur mustard and nitrogen mustard on mice.Administration of the mustard compounds led to epidermal hyperplasia and upregulation of CB 1 , CB 2 , PPARα, and fatty acid amid hydrolase (FAAH).They noted there was a significant increase in these proteins immediately after exposure to the vesicants, and the increase in CB 1 , CB 2 , and PPARα was persistent in the hyperplastic epidermis.Their results suggested CB 1 may be important in regulating keratinocyte proliferation given it was upregulated in proliferating cells whereas CB 2 may regulate keratinocyte differentiation as it was upregulated within sebaceous glands. 36Del Rio 37 developed a CB 2 and PPARγ agonist, VCE-004.8.They showed TGF-β induced collagen synthesis, deposition, and myofibroblast differentiation were decreased when cells were pretreated with VCE-004.8 and subsequently stimulated with TGF-β.Interestingly, scratch test assays showed that pretreatment with VCE-004.8 attenuated wound closure induced by TGF-β, further emphasizing the complex interplay of cannabinoid receptors and wound healing.To create an animal model of systemic scleroderma, they treated mice with bleomycin injections which increased dermal thickness and collagen content and they showed treatment with VCE-004.8 reduced skin fibrosis.Whereas when pretreated with a CB 2 or PPARγ antagonist before treatment with VCE-004.8, a reduced antifibrotic response was noted, suggesting the observed effect is dependent of both PPARγ and CB 2 . 37Casares et al. 42 evaluated the effects of CBD on HMOX1 which has several important antioxidant and anti-inflammatory properties.When keratinocyte cells were treated with CBD, there was noted to be increased HMOX1 which was likely secondary to BACH1 degradation.They also performed in vivo studies on mice using topical CBD which showed increased levels of HMOX1 and wound repair keratins in mice skin. 42hrabani et al. 38 described the beneficial effects of "new formula" (NF), a combination of sesame, wild pistachio, hemp, and walnut oil, on burn wounds in mice.They treated the burns with either nothing, NF, or silver sulfadiazine and noted the NF group had significantly increased wound contraction and decreased epithelialization time compared to the other groups. 38McIver et al. 43 treated open wounds created on limbs of horses with either unique manuka factor (UMF) 5 alone (which has minimal antimicrobial activity), UMF 20 manuka honey (which has superior antimicrobial activity), saline, or UMF 5 mixed with 1% CBD.They found no difference in healing rates.They postulated that since all horses had at least one wound treated with CBD, the CBD had a systemic anti-inflammatory effect leading to similar would healing times; however, no further testing was conducted to validate this hypothesis. 43

| Human studies
There were limited studies which examined the effects of cannabinoids on humans and wound healing.The articles identified were mainly observational studies and case reports.
Diaz et al. 49 published a case report where they described a patient who was treated with oral cannabis oil, which included a combination of CBD and THC, to treat a chronic pressure ulcer.
Specifically, the patient was administered a CBD-dominant oil once daily and two different THC-dominant oils twice daily.They noted significant improvement in the healing of the pressure ulcer at 2 weeks and almost complete closure by 2 months.A foam padded dressing was the only other intervention applied which may have confounded the effect of the cannabis oil treatment. 49Maida et al. 47,48  possible benefit in both studies, their study design did not include a control group making it difficult to determine if the TCBMs led to the wound closure. 47,48 another case series, three patients self-initiated various topical formulations of CBD to treat epidermolysis bullosa (EB) lesions.The formulations were not consistent among the cases nor was the application standardized.The patients were being treated with a variety of ineffective wound care measures, and after starting topical CBD, they reported significant improvement of pain, with reduction of opioid use as an endpoint, and concluded there was acceleration in wound healing.However, this was anecdotal and not based on objective measures. 45In an international cross-sectional study by Schraeder et al., 50 a survey was sent out to EB patients and their caretakers.Seventy-one respondents reported utilizing both topical and oral CBD in varying concentrations and in conjunction with other remedies.Pain and pruritus were self-reported to decrease by 3 points on a numerical rating scale from 0 to 10 (p < 0.001 for both) after CBD use.Most respondents reported CBD use improved their overall EB symptoms (95%), pain (94%), pruritus (91%), wound healing (81%), and decreased the use of pain medication (79%). 50lmieri et al. 46 retrospectively evaluated the effects of CBD ointment administered to patients 20 patients with moderate to severe psoriasis (five patients), atopic dermatitis (five patents), and the resulting scars from these disorders (10 patients).They were treated with an organic skin care ointment which contained CBD oil twice daily for 3 months.They objectively measured skin hydration, transepidermal water loss, and skin elasticity and noted improvements in all parameters.Additionally, they reported improvement in cutaneous blemishes and scars and fewer pustules and papules.Finally, they noted significant improvement in patient's Psoriasis Area Severity Index scores. 46

| DISCUSSION
From some of the earliest recorded history, the medicinal use of cannabis and its derivatives has been an area of keen interest.
Although many historical reports exist to profess claims of the capabilities of these compounds, only more recently has the scientific process been applied to determine what, if any, role they may have.
Here, we reviewed the available literature on cannabis and its derivatives as they relate to cutaneous wound healing.
In vitro studies have offered a variety of targets in which cannabis containing compounds may influence wound healing.
Overall, these studies suggest a positive effect on wound healing by cannabinoids.One study even utilized human skin samples and noted hypertrophic scars had lower levels of anandamide when compared to those with normal scars. 27Perhaps the most compelling of target based on these studies is CB 2 and its modulation of the acute phase inflammatory response.Later animal studies offered a potential explanation for this observation through the decreased expression of M1 macrophages in early wound healing when the wound was exposed to CB 2 agonists. 39Several subsequent studies have corroborated the beneficial effects seen with CB 2 agonists in wound healing.In addition to its effect on early inflammatory markers, CB 2 agonists appear to improve wound reepithelialization as well as lead to a decrease in fibrosis and epidermal hypertrophy. 29,34,35,37,38Although the available human studies addressing cannabinoids and skin wound healing have promising results, the relative paucity of more robust study methods (e.g., randomized control trials, prospective case-control studies, etc.) limits their applicability.Nonetheless, these studies serve as valuable proof of concept reports that future, more robust, studies may build upon.
In addition to discerning the physiologic method of action of cannabinoids and wound healing, another important avenue for research lies in medication delivery.Many of the animal studies reviewed here utilized intraperitoneal injection to deliver the experimental drug, even though systemic application may not be the ideal delivery mechanism to examine more localized effects.
These systemic administrations increase technical difficulty as well as introduce unnecessary side effects for subjects.Topical and local application can be performed by several methods including oils, ointment, paste, local injection after wound closure, or impregnation into dressings.Additionally, some formulations may allow for sustained drug delivery.For example, Zhao et al. 44 developed a hydrogel which required only one application.If further human studies do show improved wound healing after cannabinoid application, optimizing drug delivery methods will be critical to improved outcomes.
As cannabis and cannabinoid-related products become more pervasive in the lives of patients, it is important for researchers and clinicians alike to recognize this movement.Although the exact effect these compounds have on various conditions remains to be elucidated, their use should be recognized and documented in detail.
It is no longer sufficient to only screen for recreational marijuana use.
There is now a growing body of literature that demonstrates these legal over the counter and prescription compounds have active local and systemic effects that may help, or interfere with, conditions and treatments experienced by patients.Thus, further efforts must be made to accurately document the type and amount of cannabinoids a patient is utilizing.
When discussing new medical treatments, side effects must be considered.The negative systemic effects of cannabinoids are well known and include exacerbations of various psychiatric conditions and both acute and long-term cognitive deficits.They have been shown to affect the cardiovascular system and may be associated with myocardial infarction, cardiomyopathy, and sudden cardiac death.When smoked, they can have deleterious effects on the respiratory system.Additionally, they can negatively affect the reproductive system. 53Topical cannabinoid treatment will likely prevent many of the systemic side effects by directing the treatment directly to the tissue of interest.However, topical medications have a risk of acute skin reactions such as contact dermatitis or urticaria and this would also be a concern for topical cannabinoids.Interestingly, the endocannabinoid system may attenuate contact dermatitis and play a protective in these reactions. 54A recent study evaluated the dermatological side effects of topical cannabinoids, including CBD PARIKH ET AL.
| 7 of 10 and hemp seed oil.Overall, they found no significant reactions via patch testing and only saw a mild phototoxicity at 48 h when treated with hemp seed oil.The findings suggest that these products appear to be safe.However, given the various formulations that are in the market and the difficulty in regulating topical cannabinoids, these results are likely not generalizable to all cannabinoid products. 55rther research is needed to understand the full spectrum of side effects of topical cannabinoids.
discussed topical cannabis-based medicines (TCBMs) which had varying amounts of THC, THCA (delta-9 tetrahydrocannabinolic acid), and CBD.They have published two case series describing the treatment of venous stasis ulcers and nonuremic calciphylaxis ulcers with topical TCBMs.In the venous leg ulcer study, they treated 14 patients with 16 recalcitrant leg ulcers with TCBMs and compression bandaging.They reported complete closure in 11 patient and 13 wounds within a median of 34 days.In the nonuremic calciphylaxis leg ulcer study, two patients with multiple recalcitrant ulcers were treated with TCBMs.Both patients had complete closure of their wounds within a mean of 76.3 days.Although they reported a Table listing various cannabinoid agonists and antagonists.
Table summarizing the in vitro studies evaluated in this review article.Table summarizing the in vivo studies evaluated in this review article.
32eated with THC and CBD showed improved cell migration and specifically porcine primary fibroblasts showed faster wound closure 2021 Antezana et al.32Cannabis sativa extract Collagen hydrogels loaded with silver nanoparticles and C. sativa extract provided a matrix for tissue growth and showed improved biocompatibility compared to similar products without C. sativa extract Abbreviations: TGF, transforming growth factor; TNF, tumor necrosis factor.PARIKH ET AL.| 3 of 10T A B L E 3 Table summarizing the human studies evaluated in this review article.